Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Folic acid

This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate releasesolid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the WHO EssentialMedicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as “not highly soluble”. Small, physiological doses of folicacid (≤ 320 μg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified asa BCS class IV compound until more reliable data becomes available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid productsevaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot berecommended for immediate release solid oral dosage forms containing folic acid.

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